Prostate cancer is a form of cancer that develops in the prostate. Prostate cancer may cause difficulties in urinating, pain, problems during sexual intercourse, or erectile dysfunction. Moreover, the cancer cells may metastasize (spread) from the prostate to other parts of the body, particularly the lymph nodes and bones subsequently leading to pain in the back and the bones. Prostate cancer tends to develop in men over the age of fifty and it is one of the most prevalent types of cancer in men. Development of prostate cancer is influenced by many factors, including genetics and diet.
Atypical adenomatous hyperplasia (AAH) is a term that has been utilized to describe changes histologically seen in prostatic glands in the apex, periurethral region, and/or transition zone of the prostate. AAH is a localized proliferation of small acini within the prostate. Such proliferations may be confused with carcinoma, but the glands with AAH still have a fragmented basal layer. AAH can be difficult to distinguish from hyperplasia. There is a association between the presence of AAH and the development of prostate cancer.
Prostatic intraepithelial neoplasia (PIN), which is dysplasia of the epithelium lining prostate glands, is a probable precursor of prostate cancer. The appearance of PIN may precede carcinoma by 10 or more years. It can be divided into low grade and high grade PIN. Low grade PIN may be found even in men in middle age. PIN is characterized histologically by progressive basal cell layer disruption, loss of markers of secretory differentiation, nuclear and nucleolar abnormalities, increasing proliferative potential, increasing microvessel density, variation in DNA content, and allelic loss. Unlike prostate cancer, with which it may coexist, glands with PIN retain an intact or fragmented basal cell layer.
The appearance of PIN, in particular of high-grade PIN (HG-PIN) warrants increased surveillance of the prostate for development of an invasive carcinoma because the presence of HG-PIN suggests an increased risk for subsequent appearance of prostate cancer. Since HG-PIN lesions are also associated with the presence of cancer in many patients, men whose biopsies show HG-PIN are often re-biopsied until cancer is detected.
Today the only test that can fully confirm the diagnosis of prostate cancer is a biopsy, the removal of small pieces of the prostate for microscopic examination. However, prior to a biopsy, several other tools are used to gather more information about the prostate and the urinary tract before conducting this invasive method. Prostate cancers may be detected by digital examination, by transrectal ultrasonography, or by screening with a serum test for prostate specific antigen (PSA). None of these methods can reliably detect all prostate cancers, particularly the small cancers. However, if cancer is suspected, a biopsy is offered. During a biopsy a tissue sample from the prostate is obtained via the rectum. A biopsy gun inserts and removes special hollow-core needles (usually three to six on each side of the prostate). The procedure requires a local anaesthetic, and is associated with frequent complications, e.g. bleeding in the urine, bleeding in the stool, blood in the ejaculate and soreness in the biopsied area afterwards. Most men report discomfort during prostate biopsy (Essink-Bot, M L et al. J Natl Cancer Inst 90: 925-31). The tissue samples are then examined under a microscope to determine histopathologically whether cancer cells are present, and to evaluate the morphologic features (Gleason score) of any cancer found (Gleason D F. in Tannenbaum M (ed.) Urologic Pathology: The Prostate. Lea and Febiger, Philadelphia, 1977; 171-198).
Hepsin (HPN/TMPRSS1 (GeneID 3249); mRNA (NM—002151; SEQ ID NO. 1) or (NM—182983; SEQ ID NO. 36)) is a membrane serine protease that is highly expressed in prostate tissue. Expression profiling studies of mRNA have also shown an over-expression of hepsin in 90% of the analyzed prostate cancers (Stephan et al. 2004; J Urol.; 171(1):187-91). Another study using immunohistochemistry showed hepsin to be highly produced in PIN lesions and to be preferentially produced in prostate cancer compared with benign prostatic hyperplasia (BPH) (Dhanasekaran et al 2001). However, the lack of detection of hepsin in blood, serum or urine limits its role as a biomarker so far (Parekh et al. 2007; J Urol.; 178(6):2252-9; Sardana et al. 2008 Clin Chem.; 54(12):1951-60; Kelly et al. 2008. Cancer Res.; 68(7):2286-91; Morrissey et al. 2008, Clin Exp Metastasis; 25(4):377-88.)
At present, an active area of research involves non-invasive methods of prostate cancer detection. A method of early prostate tumor detection is a test for the presence of cell-associated PCA3 (prostate cancer antigen 3, formerly DD3, GeneID 50652, non-coding RNA NR—015342 (SEQ ID NO. 4) or RNA AF103907 (SEQ ID NO. 5)) mRNA in urine. PCA3 mRNA is expressed almost exclusively by prostate cells and has been shown to be highly over-expressed in prostate cancer cells. Thus, PCA3 is an additional tool to help decide whether, in men suspected of having prostate cancer, a biopsy is really needed. The higher the concentration of PCA3 in urine, the greater the likelihood of a positive biopsy, i.e. the presence of cancer cells in the prostate. However, the disadvantages of this method are the still unsatisfactory rates for sensitivity and specificity (Kirby et al. 2009; BJU Int.; 103(4):441-5.).
A further commonly used test to asses the presence of prostate cancer is the Prostate Specific Antigen (PSA) (kallikrein-related peptidase 3, KLK3, GeneID 354, mRNA transcript variant 1 NM—001648 (SEQ ID NO. 3) or transcript variant 3 NM—001030047 (SEQ ID NO. 37 or transcript variant 5 NM—001030049 (SEQ ID NO. 38)) test. The PSA test measures the blood level of prostate-specific antigen, an enzyme produced by the prostate. Increased PSA levels correlate with an increased risk for prostate cancer (Cataluna W J. “How I manage a patient with a newly elevated PSA”, 2007, CDC Cancer Conference. http://www.cdccancerconference.net/Presentations/ET2.0/ET2.0_Catalona.pdf). 4 ng/mL was chosen arbitrarily as a decision level for biopsies in the clinical trial upon which the FDA in 1994 based adding prostate cancer detection in men age 50 and over as an approved indication for the first commercially available PSA test. 4 ng/mL was used as the biopsy decision level in the PLCO trial, 3 ng/mL was used in the ERSPC and ProtecT trials, and 2.5 ng/mL is used in the 2007 NCCN guideline.
PSA levels can change for many reasons other than cancer. Two common causes of high PSA levels are enlargement of the prostate (BPH) and inflammation in the prostate (prostatitis). It can also be raised for 24 hours after ejaculation and several days after catheterization. Even though widely used, PSA levels can not alone be a reliable marker for diagnosis of prostate cancer.
Regardless by which test the probability of the presence of prostate cancer is determined, the diagnosis has to be confirmed by taking a biopsy of the prostate and examining it under a microscope.
Thus, there is need for a reliable, non-invasive method for the diagnosis of prostate cancer which affords both, sensitivity and specificity, i.e. minimizing false positive and false negative diagnosis.